This invention relates to a controlled or sustained release formulation designed to deliver a PDE4 inhibitor which preferentially inhibits, or binds, one form of a phosphodiesterase isozyme denominated 4 (PDE 4 hereafter) while exhibiting equal or, preferably less binding or inhibition for a second form of the enzyme.
In the area of respiratory diseases, at least two diseases stand out as increasing in frequency and being difficult to treat, asthma and chronic obstructive pulmonary disease or COPD. While these diseases have different etiologies and different pathologies, they share a common challenge: providing effective prophylatic treatment or providing a single highly effective treatment of symptoms, particularly one with minimal side effects. One recent approach is that of a new generation of drugs targeting the cyclic nulceotide phosphodiesterases.
Cyclic nucleotide phosphodiesterases (PDEs) represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) and guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) to their corresponding inactive 5xe2x80x2-monophosphate metabolites. At least seven distinct classes of PDE isozymes are believed to exist, each possessing unique physical and kinetic characteristics and each representing a product of a different gene family. These are distinguished using Arabic numerals 1-7.
The target enzyme for use of the formulations of this invention is the PDE 4 isozyme in all its various forms and in the full domain of its distributions in all cells. It is a low Km (cAMP Km=1-5 xcexcM) cAMP-selective enzyme that has little activity against cGMP (Km greater than 100 xcexcM). Members of this isozyme class have the interesting characteristics of existing in two or more non-interconvertible or slowly interconvertible forms that bind rolipram and other PDE IV inhibitors with distinct rank-order potencies. Thus the same gene product can exist in more than one catalytically active conformational state. Importantly, the relative proportions of the different binding forms may vary depending on the tissue cell type. For example, inflammatory cells may contain a relatively high proportion of the form that binds rolipram with a low affinity while brain and parietal cells may contain a relatively high proportion of the form that binds rolipram with a high affinity. Current PDE inhibitors used in treating inflammation and as bronchodilators, drugs like theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminately in all tissues. These compounds exhibit side effects, apparently because they non-selectively inhibit all PDE isozyme classes in all tissues. The targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states. Although in theory isozyme-selective PDE inhibitors should represent an improvement over non-selective inhibitors, the selective inhibitors tested to date are not devoid of side effects produced as an extension of inhibiting the isozyme of interest in an inappropriate or untargeted tissue. For example, clinical studies with the selective PDE 4 inhibitor rolipram, which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis. Indications are that side effects of denbufylline, another PDE 4 inhibitor targeted for the treatment of multi-infarct dementia, may include pyrosis, nausea and emesis as well. These side effects are thought to occur as a result of inhibiting PDE 4 in specific areas of the CNS and gastrointestinal system.
But it has been found that certain compounds which potently compete for the high affinity rolipram binding form (HPDE 4) have more side effects or more intense side effects than those which more potently compete with the LPDE 4 (low affinity rolipram binding form). Data is now available which indicate that compounds can be targeted to the low affinity binding form of PDE 4 and that this form is distinct from the binding form for which rolipram is a high affinity binder. Distinct SARs have been found to exist for inhibitors acting at the high affinity rolipram binding form versus the low affinity rolipram binding form. In addition, these two forms appear to have different functional roles. Thus compounds that interacted with the low affinity rolipram binding form appear to have anti-inflammatory activity, whereas those that interact with the high affinity rolipram binding form produce side effects or exhibit more intensely those side effects.
A useful consequence of these findings is that it is now possible to identify compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. This provides a superior therapeutic index vis-a-vis anti-inflammatory and or bronchodilator activities versus side effects.
While to date no one has been able to identify a compound which is completely without unwanted CNS side effects at all possible dosage levels, at least one compound has been identified that meets the criteria described above, namely cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid. And while this compound has a therapeutic ratio of greater than 0.1 and can be administered orally and achieve an effective therapeutic effect in COPD at certain doses, it has been found that as blood levels increase with increased levels of dosing, undesirable side effects such as those attributed to CNS activity begin to be manifested. Increasing the initial dose has been studied to determine whether or not superior treatment can be provided by increasing blood levels at a higher concentration for a longer period of time since respiratory diseases are often chronic, not episodic. This is particularly true with COPD. It has been found that the dose level and length of effective treatment, while avoiding side effects, can be achieved by using a controlled or sustained release formulation. The controlled release formulations of this invention allow for administering in a single dosage form several times the quantity that can otherwise be administered of a PDE4 inhibitor and achieve both initial therapeutically effective blood levels and maintain these blood level for an extended period of time. PDE4 inhibitors, particularly PDE4-specific inhibitors are useful in treating other diseases especially in the areas of inflammation, (e.g., asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, rheumatoid arthritis), affects related to tumor necrosis factor and to cognition impairment (e.g., multi-infarct dementia, cognitive dysfunction, or stroke). This invention is useful in treating these diseases as well. These formulations and the method described herein can be used for prophylactic treatment as well. Additional other therapeutic or prophylactic agents can be combined with a PDE4 inhibitor in these formulations as well.
In a first aspect this invention relates to a pharmaceutically formulation for treating effectively inflammation in a mammal with a PDE4 inhibitor while avoiding adverse events, the process comprising mixing a pharmaceutically acceptable excipient capable of forming a controlled-release formulation with a therapeutically effective amount of a PDE4 inhibitor, which amount if administered as an immediate release preparation would clause adverse events.
In a further aspect this invention relates to a method for administering a PDE4 inhibitor in a prophylactically effective, non-emesis-causing amount for up to about 24 hours for use in the prophylaxis of a disease susceptible of to being warded off by the administration of a PDE4 ihnibitor, which method comprises confecting said compound with at least one pharmaceutically acceptable excipient capable of forming a controlled release formulation containing said compound.
In another aspect this invention relates to an improved method for preventing the onset of or treating a human suffering from a diseases which can be treated by inhibiting the PDE 4 enzyme wherein the improvement comprises confecting and/or administering a controlled release formulation comprising said compound with at least one pharmaceutically acceptable excipient capable of forming a controlled release formulation with said compound wherein said formulation has a release profile that provides a therapeutically effective, non-emisis-causing concentration of said drug in said subject for up to about 24 hours.
In yet a further aspect, this invention relates to the manufacture of a pharmaceutically acceptable dosage form which is a controlled release formulation comprising mixing a PDE 4 inhibitor with at least one excipient capable of forming a controlled release composition with said compound wherein said dosage form has a release profile that provides a therapeutically effective, non-emisis causing concentration of said drug in said subject for up to about 24 hours.
In yet another aspect, this invention relates to a method for treating inflammation or for dilating bronchi, particularly in regards to treating asthma or COPD, by administering a controlled release formulation containing a PDE 4 inhibitor wherein said formulation has a release profile that provides a therapeutically effective, non-emisis-causing concentration of said drug in said subject for up to about 24 hours.
This invention also relates to a stable controlled release formulation comprising a Carbopol polymer, drug, dibasic calcium phosphate, optionally other excipients and between about 0.5-2.0% weight/weight of water.